The present disclosure relates generally to a wide concentration range of anti-prolactin receptor antibody formulations that are substantially isosmotic and of low viscosity, including formulations that are useful for subcutaneous and general injection administration.
Prolactin (PRL) is a polypeptide hormone composed of 199 amino acids. PRL belongs to the growth hormone (GH), placental lactogen (PL) family of polypeptide hormones and is synthesized in lactotroph cells of the pituitary and in several extrapituitary tissues such as lymphocytes, mammary epithelial cells, the myometrium, and the prostate. Two different promoters regulate pituitary and extrapituitary PRL synthesis (BioEssays 28:1051-1055 (2006)).
PRL binds to the PRL receptor (PRLR), a single transmembrane receptor belonging to the class 1 cytokine receptor superfamily (Endocrine Reviews 19:225-268 (1998)). PRLR exists in three different isoforms, the short, the long, and the intermediate form that can be distinguished by the length of their cytoplasmic tails. Upon ligand binding, a sequential process leads to PRLR activation. PRL interacts via its binding site 1 with one PRLR molecule and then attracts via its binding site 2 a second receptor molecule leading to an active dimer of PRLRs.
PRLR dimerization leads to the predominant activation of the JAK/STAT (Janus Kinase/Signal transducers and activators of transcription) pathway. Upon receptor dimerization, JAKs (predominantly JAK2) associated with the receptor, transphosphorylate and activate each other. In addition the PRLR is also phosphorylated and can bind to SH2-domain containing proteins such as STATs. Receptor bound STATs are subsequently phosphorylated, dissociate from the receptor and translocate to the nucleus where they stimulate transcription of target genes. In addition, activation of the Ras-Raf-MAPK pathway and activation of the cytoplasmic src kinase by PRLRs have been described (for review Endocrine Reviews 19: 225-268 (1998)).
The role of PRLR-mediated signalling has been investigated in the context of the benign disease endometriosis. In one study the expression pattern of the PRLR in endometriotic samples and eutopic endometrium from endometriosis patients was analysed (Acta Obstet Gynecol Scand 81:5-10, 2002) during the mid-late proliferative phase of the menstrual cycle. It was demonstrated that the PRLR mRNA was present in the eutopic endometrium in 79% of the analysed endometriosis patients, whereas it was absent in the endometriotic lesions in 86% of the endometriosis patients. These data suggested a possible differential regulation of PRLR expression between normal and endometriotic tissue. However, from these expression data it cannot be concluded that inhibition of the PRLR might represent a suitable endometriosis therapy—especially since the PRLR was not found to be expressed in the endometriotic lesions (Acta Obstet Gynecol Scand 81:5-10 (2002)).
Antibodies that are directed against prolactin receptor (PRLR), including anti-PRLR monoclonal antibodies (aPRLR mAbs), are being developed in an effort to block PRLR function. One such aPRLR mAb is an IgG2 anti-PRLR mAb that is being developed for the non-hormonal treatment of endometriosis patients.
Antibodies may be administrated to patients via intravenous, intramuscular, and/or subcutaneous injection. To ensure patient compliance, it is desirable that intramuscular and subcutaneous injection dosage forms be isotonic and include small injection volumes (<2 ml per injection site). To reduce injection volume, and to provide an effective dose, antibodies are often administered with a wide concentration range, from 0.1-150 mg/mL, including high concentrations within the range of 20 mg/ml to 150 mg/ml.
While both liquid and lyophilized dosage forms are used for currently marketed antibody drug products, lyophilized forms are more frequently used for antibody drug products having high protein concentrations. A high concentration antibody dosage form may present many challenges in formulation development, especially for liquid formulation. For formulations in which the antibody concentration is near its apparent solubility limit, phase separation can occur through precipitation, gelation, and/or crystallization. At high protein concentration, the stability of an antibody can become problematic due to the formation of soluble and insoluble protein-protein aggregates. Highly concentrated antibody formulations are frequently highly viscous, which presents difficulties for processing, such as ultrafiltration and sterile filtration, and for injection of the dosage solution. And at high antibody concentrations, which are desirable for formulations intended for intramuscular or subcutaneous administration, proportionally high concentrations of stabilizers, such as sucrose and sodium chloride, are required to achieve long-term protein stability. The resulting hypertonic solutions often cause injection pain due to tissue damage. Therefore, it is often desirable to balance the amount of stabilizers for stability and osmolality of the high protein concentration formulation.